Lipid metabolism ameliorants

ABSTRACT

The present invention relates to a food and a feed having lipid metabolism improving activity or anti-obesity activity, and a lipid metabolism improving agent or an anti-obesity agent for humans or animals which comprise, as an active ingredient, a compound represented by formula (I): ##STR1## wherein &gt;A--B-- represents &gt;CR 1  --NR 2  -- (wherein R 1  represents hydrogen or hydroxy, and R 2  represents hydrogen or lower alkyl; or R 1  and R 2  are combined together to form a bond) or &gt;C═N +  (R 3 )-- (wherein R 3  represents lower alkyl); n represents 0 when &gt;A--B-- is &gt;CR 1  --NR 2  --, and represents 1 when &gt;A--B-- is &gt;C═N +  (R 3 )--; and X -   represents an anion, or a salt thereof.

TECHNICAL FIELD

The present invention relates to a food, a drug and a feed which havelipid metabolism improving activity or anti-obesity activity.

BACKGROUND ART

The term lipid metabolism refers to the in vivo process of catabolism(decomposition) and anabolism (accumulation) of lipids, which are mainlytriglycerides derived from food, and is intended to include, in thebroad sense, reactions for transforming lipids into energy, biosynthesisof fatty acids, biosynthesis of acylglycerol, phospholipid metabolism,and cholesterol metabolism.

The term obesity means an excessive accumulation of fat in fat tissuesof the parts of the body, and obesity is known to be closely related tohypertension, hyperlipidemia, diabetes, cerebral apoplexy,arteriosclerosis, myocardial infarction, etc.

Anti-obesity measures, or measures to treat or prevent obesity can bebroadly classified into two groups; that is, control of energy intakeand promotion of energy consumption. Examples of the former are intakeof substitutes for sugar and fat, intake of dietary fibers contained infoods such as konjak (devil's-tongue jelly), and intake ofabsorption-inhibiting substances or appetite-depressing substances suchas Gymnema sylvestre (Japanese Published Unexamined Patent ApplicationNo. 343421/94). Examples of the latter are exercise, and intake of lipidmetabolism improving agents such as capsaicin (Japanese PublishedExamined Patent Application No. 58303/92) and soybean peptides {DaizuTanpakushitsu Eiyo Kenkyukai Kaishi [Nutritional Science of Soy Protein(Japan)], 13, 53-58 (1992)}. However, it is difficult to continueexercise, and there is a limitation to capsaicin intake because of itshot taste. Thus, a need exists for a development of an effective lipidmetabolism improving agent.

At present, rich feed is administered to livestock, poultry andcultivated fish with the aim of promoting their growth. As a result, alipid metabolism abnormality sometimes occurs in these livestock,poultry and cultivated fish. As for pets, an excessive intake of feedand lack of exercise sometimes cause the problem of obesity.

Evodiamine is a compound obtained from Evodia rutaecarpa of the familyRutaceae, which is a kind of crude drug [Journal of PharmaceuticalSciences, 75, 612-613 (1986)].

Evodiamine is known to have various pharmacological activities, forexample, activities as a chilly constitution improving agent (JapanesePublished Unexamined Patent Application No. 305527/92), a brain functionimproving agent (Japanese Published Unexamined Patent Application No.287724/88), an anti-inflammatory agent for external use (JapanesePublished Unexamined Patent Application No. 312932/94) and a cardiotonic(Japanese Published Unexamined Patent Application No. 224622/85),vasorelaxation activity [European Journal of Pharmacology, 215, 277-283(1992)], and analgesic activity [Biol. Pharm. Bull., 20(3), 243-248(1997)], as well as diuretic activity and sweating activity. However,there has been no report on lipid metabolism improving activity oranti-obesity activity thereof.

Rutaecarpine, dehydroevodiamine and hydroxyevodiamine are structurallyanalogous compounds which are obtained from Evodia rutaecarpa as well asevodiamine. The former two compounds have vasorelaxation activity likeevodiamine [European Journal of Pharmacology, 257, 59-66 (1994), J.Cardiovasc. Pharmacol., 27(6), 845-853 (1996)]. Further, rutaecarpinehas analgesic activity as well as evodiamine [Biol. Pharm. Bull., 20(3),243-248 (1997)]. However, there has been no report on the above threecompounds in respect of lipid metabolism improving activity oranti-obesity activity.

Evodia rutaecarpa, which is a plant belonging to the genus Evodia, isnot only used as a stomachic, a diuretic and an analgesic, but also isknown to have activities as a hair-nourishing food (Japanese PublishedUnexamined Patent Application No. 1619/86), cosmetics containing extractof Evodia rutaecarpa (Japanese Published Unexamined Patent ApplicationNo. 122414/84), an alcohol absorption-inhibiting agent (JapanesePublished Unexamined Patent Application No. 264534/91), and atherapeutic agent for periodontal disease (Japanese Published UnexaminedPatent Application No. 148426/87). However, there has been no report onlipid metabolism improving activity or anti-obesity activity thereof.

Fagara rhetza, which is an Indonesian traditional medicinal herbbelonging to the genus Fagara, is known to have an effect on malaria,diarrhea and vomiting [Chem. Pharm. Bull., 40(9), 2325-2330 (1992)].However, no report has been made on lipid metabolism improving activityor anti-obesity activity thereof.

Zanthoxylum rhetsa and Zanthoxylum budrunga, which are plants belongingto the genus Zanthoxylum, have been reported to have cytotoxicity [J.Nat. Prod., 42(6), 697 (1979)]. However, no report has been made onlipid metabolism improving activity or anti-obesity activity thereof.

Araliopsis tabouensis and Araliopsis soyauxii, which are plantsbelonging to the genus Araliopsis, are known to have an effect ongonorrhea [Planta medica, 29, 310-317 (1976)]. However, no report hasbeen made on lipid metabolism improving activity or anti-obesityactivity thereof.

DISCLOSURE OF THE INVENTION

The present invention relates to a food having lipid metabolismimproving activity or anti-obesity activity which comprises, as anactive ingredient, a compound selected from the group consisting ofcompounds represented by formula (I): ##STR2## wherein >A--B--represents >CR¹ --NR² -- (wherein R¹ represents hydrogen or hydroxy, andR² represents hydrogen or lower alkyl; or R¹ and R² are combinedtogether to form a bond) or >C═N⁺ (R³)-- (wherein R³ represents loweralkyl); n represents 0 when >A--B-- is >CR¹ --NR² --, and represents 1when >A--B-- is >C═N⁺ (R³)--; and X⁻ represents an anion, and saltsthereof (hereinafter collectively referred to as evodiamine compounds).

The present invention also relates to a lipid metabolism improving agentor an anti-obesity agent which comprises an evodiamine compound as anactive ingredient; a method for lipid metabolism improvement oranti-obesity which comprises administering an effective amount of anevodiamine compound; the use of an evodiamine compound for thepreparation of a pharmaceutical composition which is useful for lipidmetabolism improvement or anti-obesity; the use of an evodiaminecompound for lipid metabolism improvement or anti-obesity; and acomposition for lipid metabolism improvement or anti-obesity whichcomprises, in pharmaceutically acceptable dosage form, an effectiveamount of an evodiamine compound in association with a pharmaceuticallyacceptable carrier.

Further, the present invention relates to a feed having lipid metabolismimproving activity or anti-obesity activity which comprises anevodiamine compound as an active ingredient.

Furthermore, the present invention relates to a feed additive havinglipid metabolism improving activity or anti-obesity activity whichcomprises an evodiamine compound as an active ingredient; a method forlipid metabolism improvement or anti-obesity of an animal whichcomprises administering an effective amount of an evodiamine compound;the use of an evodiamine compound for the preparation of a feed additivewhich is useful for lipid metabolism improvement or anti-obesity; theuse of an evodiamine compound for lipid metabolism improvement oranti-obesity of an animal; and a composition for lipid metabolismimprovement or anti-obesity of an animal which comprises, inpharmaceutically acceptable dosage form, an effective amount of anevodiamine compound in association with a pharmaceutically acceptablecarrier.

In the definitions of the groups in formula (I), the lower alkylrepresented by R² and R³ means a straight-chain or branched alkyl grouphaving 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl. Preferred ismethyl.

Examples of the anions are hydrogen ion, halogen ions, anions derivedfrom inorganic acids and anions derived from organic acids. Examples ofthe halogen ions are fluorine ion, chlorine ion, bromine ion and iodineion. Examples of the anions derived from inorganic acids are nitrateion, sulfate ion, phosphate ion and carbonate ion. Examples of theanions derived from organic acids are formate ion, acetate ion, lactateion, citrate ion, and anions derived from carboxylic acids such asglutamic acid.

Examples of the salts are acid addition salts, e.g. hydrochloride, andorganic acid addition salts such as maleate, tartrate and citrate.

The evodiamine compounds represented by formula (I) include evodiamine,rutaecarpine, dehydroevodiamine, hydroxyevodiamine, etc.

Evodiamine is a compound represented by formula (II): ##STR3##

Evodiamine is commercially available (a product of Kishida Chemical Co.,Ltd.). It can also be prepared according to the chemical synthesismethods described in Japanese Published Unexamined Patent ApplicationNo. 77098/77, Japanese Published Examined Patent Application No. 434/83[(R,S)-evodiamine], J. Chem. Soc. Chem. Commun. 10, 1092-1093 (1982)[(S)-evodiamine], etc., or can be obtained from evodiamine-containingplants, for example, plants belonging to the family Rutaceae such asplants of the genus Evodia (Evodia rutaecarpa, E. officinalis, E.danielli, E. meliaefolia, etc.), the genus Fagara (Fagara rhetza, etc.),the genus Zanthoxylum (Zanthoxylum rhetsa, Z. budrunga, Z. flavum,etc.), and the genus Araliopsis (Aralioisis tabouensis, A. soyauxii,etc.) according to, for example, the method described in Journal ofPharmaceutical Sciences, 75, 612-613 (1986).

Evodiamine has optical isomers: both the S-form and the R-form areobtained according to the chemical synthesis methods, and the S-form isobtained from the plants. In the present invention, any of the S-form,the R-form, and the mixture thereof may be used. Preferred is theS-form.

Rutaecarpine is a compound represented by formula (III): ##STR4##

Rutaecarpine is commercially available (a product of Kishida ChemicalCo., Ltd.). It can also be prepared according to the chemical synthesismethods described in Japanese Published Unexamined Patent ApplicationNo. 77100/78, J. Org. Chem., 50, 1246-1255 (1985), etc., or can beobtained from rutaecarpine-containing plants, for example, plantsbelonging to the family Rutaceae such as plants of the genus Evodia(Evodia rutaecarpa, E. meliaefolia, etc.), the genus Fagara (Fagararhetza, etc.), and the genus Zanthoxylum (Zanthoxylum rhetsa, Z.limonella, Z. integrifoliolum, etc.) according to, for example, themethod described in Chem. Pharm. Bull., 37, 1820-1822 (1989).

Dehydroevodiamine is a compound represented by formula (IV): ##STR5##wherein X⁻ represents an anion, which has the same significance asdescribed above. Dehydroevodiamine can be prepared according to thechemical synthesis method described in J. Org. Chem., 50, 1246-1255(1985), etc., or can be obtained from dehydroevodiamie-containingplants, for example, plants belonging to the family Rutaceae such asplants of the genus Evodia (Evodia rutaecarpa, E. meliaefolia, etc.)according to, for example, the method described in American Journal ofChinese Medicine, 10, 75-85 (1982).

Hydroxyevodiamine is a compound represented by formula (V): ##STR6##

Hydroxyevodiamine can be obtained from hydroxyevodiamine-containingplants, for example, plants belonging to the family Rutaceae such asplants of the genus Evodia (Evodia rutaecarna, etc.), the genusZanthoxylum (Zanthoxylum rhetsa, etc.), and the genus Araliopsis(Araliopsis tabouensis, etc.) according to, for example, the methoddescribed in J. of the Pharmaceutical Society of Japan, 82, 619-626(1962).

As the evodiamine compounds in the present invention, purified productsor pure preparations can be used, but crude ones or partially-purifiedones may also be used as long as they do not contain impurities whichare inappropriate as components of foods, drugs or feeds.

Examples of the crude or partially-purified evodiamine compounds areparts (e.g. leaves, trunks, bark, roots and fruits) of plants whichcontain evodiamine compounds, preferably plants belonging to the familyRutaceae, more preferably plants belonging to the genus Evodia, Fagara,Zanthoxylum or Araliopsis, and ground matters, extracts, crude productsand purified products containing evodiamine compounds which are obtainedfrom said parts of the plants.

As the parts of the plants containing evodiamine compounds, fruits, barkand root bark of the plants such as Evodia rutaecarpa, Fagara rhetza,Zanthoxylum rhetsa, Araliopsis tabouensis and Evodia meliaefolia arepreferably used.

The ground matters containing evodiamine compounds can be obtained bydrying and then grinding the parts of the plants containing evodiaminecompounds.

The extracts containing evodiamine compounds can be obtained byextraction from said ground matters using water, hydrophilic solvents,e.g. alcohols such as methanol, ethanol, propanol and butanol, andacetone, and organic solvents such as diethyl ether, ethyl acetate,chloroform and benzene, alone or in combination.

The partially-purified or purified products of evodiamine compounds canbe obtained by subjecting said ground matters or extracts to fractionalpurification by means of column chromatography or preparative high 35performance liquid chromatography using a porous polymer such as DIAIONHP-20 (registered trademark, Mitsubishi Chemical Co., Ltd.), Sephadexsuch as Sephadex LH-20 (registered trademark, Pharmacia LKBBiotechnology Co., Ltd.), normal phase silica gel, reversed-phase silicagel, polyamide, activated carbon or cellulose. In this purificationstep, detection of the desired component is carried out by thin layerchromatography (developing solvent: 95% methanol, color developingagent: 5% ethanol sulfate). It is desirable to appropriately combine orrepeat the above treatments, and if necessary, to carry outrecrystallization in order to prepare the purified products or the purepreparations of evodiamine compounds.

The food of the present invention can be prepared by adding anevodiamine compound to food materials, particularly, those containingsubstantially no evodiamine compound by nature in a conventional processfor producing a food. The evodiamine compound is added in the form of apure preparation, a purified product, a partially-purified product, alipid metabolism improving agent or an anti-obesity agent, in such anamount that the content of the compound in the food becomes 0.001% ormore, preferably 0.01-20%, more preferably 0.05-1%.

Examples of the foods are juice, soft drinks, tea, lactic acidbeverages, fermented milk, ices, dairy products (e.g. butter, cheese,yogurt, processed milk and skim milk), meat products (e.g. ham, sausageand hamburger), fish products (e.g. steamed, baked or fried fish paste),egg products (e.g. fried or steamed foods made of beaten eggs),confectionery (e.g. cookies, jelly and snacks), bread, noodles, pickles,smoked fish and meat, dried fish, preserved foods boiled down with soy,salted foods, soup and seasonings.

The food of the present invention may be in any of the forms such as afrozen food, a powder food, a sheet-shaped food, a bottled food, acanned food, a retort food, a capsule food and a tablet food, and mayalso be in the form of a liquid food, a pre-digested nutrient food, anelemental diet, a liquid nutrient food, or the like formulated tocontain a protein, a sugar, a fat, a trace element, a vitamin, anemulsifier, a flavor, etc., as long as the food contains an evodiaminecompound.

The food of the present invention can be used as a health food or afunctional food not only for slimming diet but also for the treatment,prevention or alleviation of diseases such as fatty liver, hypertension,hyperlipidemia, arteriosclerosis, diabetes and myocardial infarction. Itis preferred that an evodiamine compound is ingested in an amount of0.1-2000 mg/day from the processed food of the present invention.

The lipid metabolism improving agent or the anti-obesity agent of thepresent invention may be in any of the dose forms such as tablets,powders, fine granules, granules, capsules, syrups, enteric coatedtablets, troches, injections and infusions. The administration route forsaid agent is not specifically limited. Examples of suitableadministration routes are oral administration, intravenousadministration, intraperitoneal administration, subcutaneousadministration and intramuscular administration. Preferred is oraladministration. In the case of oral administration, a pure preparation,a purified product or a partially-purified product of an evodiaminecompound can be administered as it is, or in the form of compositionssuch as tablets, powders, fine granules, granules, capsules and syrupcontaining pharmaceutically acceptable excipients. As the excipients,saccharides such as sorbitol, lactose, glucose, dextrin, starch andcrystalline cellulose, inorganic substances such as calcium carbonateand calcium sulfate, distilled water, sesame oil, corn oil, olive oil,cottonseed oil, and other generally employed excipients can be used. Inpreparing the compositions, additives such as binders, lubricants,dispersing agents, suspending agents, emulsifiers, diluents, buffers,antioxidants and antibacterial agents may be used. Injectablepreparations can be prepared by adding an appropriate buffer, anisotonicity agent, etc. to an active compound and dissolving the mixturein an oil such as a vegetable oil.

The dose of said agent will vary depending on various factors such asthe patient's age, sex and physical condition, administration route,administration schedule, and form of the agent. For instance, when theagent is orally administered to an adult, it is suitable to administeran evodiamine compound as an active ingredient in an amount of 0.1-2000mg/day in 1 to 4 parts. Administration may be made at a dose outside theabove limit as may be required.

The lipid metabolism improving agent or the anti-obesity agent of thepresent invention can be used for the treatment or prevention ofdiseases such as fatty liver, hypertension, hyperlipidemia,arteriosclerosis, diabetes and myocardial infarction, and obesity.

The feed of the present invention includes any feed comprising anevodiamine compound which has lipid metabolism improving activity oranti-obesity activity on animals such as mammals, birds, reptiles,amphibians and fish. Suitable examples are feed for pets such as dogs,cats and mice, feed for livestock such as cows and pigs, feed forpoultry such as hens and turkeys, and feed for cultivated fish such assea breams and young yellowtails.

As the feed additive of the present invention, any of the followingsubstances can be used: an evodiamine compound in the form of a purepreparation, a purified product or a partially-purified product; partsof plants containing an evodiamine compound; and a ground matter,extract, a partially-purified product or a purified product containingan evodiamine compound which is obtained from said plant parts. Ifnecessary, the feed additives may be made into the form of powder, finegranules, pellets, tablets, various liquids, etc. by mixing ordissolution in a conventional manner.

The feed of the present invention can be prepared by adding the abovefeed additive to a feed. The amount of the feed additive of the presentinvention to be added to the feed is appropriately selected depending onthe kind of feed, the effect expected by intake of the feed, etc.Generally, the feed of the present invention can be prepared by addingthe feed additive of the present invention to feed materials,particularly, those containing substantially no evodiamine compound bynature in a conventional process for producing a feed, in such an amountthat the content of an evodiamine compound in the feed becomes 0.001% ormore, preferably 0.01-20%, more preferably 0.05-1%.

TEST EXAMPLE 1

Effect on Visceral Fat of a Mouse

The following experiment was carried out using a feed containingevodiamine.

Nine-weeks-old male C3H mice were preliminarily fed with Feed Acontaining no evodiamine which was prepared according to the compositionof Table 1 for 8 days, and then divided into 2 groups each consisting of4 animals. One of the groups (Feed A group) was fed with Feed A and theother group (Feed B group) was fed with Feed B containing evodiaminewhich was prepared according to the composition of Table 1 for 12 days.After being fasted for one day, the mice of both groups were killed onthe 13th day. The perirenal adipose tissue and the epididymal adiposetissue of each mouse were excised immediately and weighed. The feedintake was measured every day during the test period.

                  TABLE 1                                                         ______________________________________                                                       Feed A Feed B                                                    % (w/w) % (w/w)                                                             ______________________________________                                        Evodiamine       --       0.03                                                  Casein 20 20                                                                  Lard 10 10                                                                    Sucrose 10 10                                                                 Mineral mixture 4 4                                                           Vitamin mixture 1 1                                                           Cellulose powder 2 2                                                          Sodium cholate 0.125 0.125                                                    Choline chloride 0.2 0.2                                                      Corn starch 52.675 52.645                                                   ______________________________________                                    

The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                                     Feed A group                                                                           Feed B group                                            ______________________________________                                        Average feed intake                                                                           3.30 ± 0.08*                                                                         3.21 ± 0.09                                        (g/day)                                                                       Epididymal adipose 0.246 ± 0.019 0.219 ± 0.010                          tissue (g)                                                                    Perirenal adipose 0.116 ± 0.01.sup.a 0.083 ± 0.08                       tissue (g)                                                                  ______________________________________                                         *Standard error of the average value                                          .sup.a The difference between the two groups was significant (P < 0.05)  

The amount of the perirenal adipose tissue in Feed B group wassignificantly smaller than that in Feed A group. The amount of theepididymal adipose tissue was also somewhat smaller in Feed B group.There was no significant difference in feed intake between the twogroups, which suggests that there is no taste problem. Thus, it wasconfirmed that evodiamine had lipid metabolism improving activity oranti-obesity activity.

TEST EXAMPLE 2

Effect on Weight, Visceral Fat and Lipolysis of a Rat

The following experiment was carried out using a feed containing extractof Evodia rutaecarpa prepared in Reference Example 1.

Four-weeks-old male SD rats were preliminarily fed with low-fat Feed Ccontaining no extract of Evodia rutaecarpa which was prepared accordingto the composition of Table 3 for 7 days. The rats were then dividedinto 9 groups each consisting of 3 animals in such a way that there isno significant difference in body weight of the animals among thegroups. One rat in each group was fed with Feed E which is a high-fatfeed containing the extract of Evodia rutaecarpa after one-day fast. Theother two rats in each group were given, by pair-feeding, Feed C whichis a low-fat feed without the extract of Evodia rutaecarpa and Feed Dwhich is a high-fat feed without the extract of Evodia rutaecarpa,respectively, in an amount equal to the feed intake of the rat fed withFeed E in the same group. As Feed C and Feed E have different fatcontents, when they are taken in the same amounts, the calorie intakefrom Feed C is about 78% of that from Feed E. After the breeding by theabove pair-feeding was continued for 21 days, the rats were fasted forone day and then killed. The perirenal adipose tissue and the epididymaladipose tissue of each rat were excised immediately and weighed. Thelipolytic activity was also determined in the following manner. The bodyweight was measured every day during the test period.

Determination of the Lipolytic Activity:

After the perirenal adipose tissue of each rat was cut into pieces withscissors 50 times, 100-300 mg of the cut tissue was weighed, and 1.9 mlof Krebs-Ringer bicarbonate buffer (hereinafter abbreviated as KRBbuffer) containing 2% albumin was added thereto to prepare two samples.These samples were subjected to reaction at 37° C. for 5 minutes. To oneof the samples was added 0.1 ml of KRB buffer containing 0.2 mg/mlnoradrenaline-2% albumin, and the mixture was subjected to reaction at37° C. for one hour to make a reaction sample. To the other sample wasadded 0.1 ml of KRB buffer containing 2% albumin, and the mixture wasice-cooled for 5 minutes to make a pre-reaction control sample. Eachsample was filtered using a membrane filter (0.45 μm, Millipore Corp.)and the amount of free fatty acids in the filtrate was determined usinga commercially available determination kit (Determiner NEFA, Kyowa MedexCo., Ltd.). Then, the amount of triglycerides decomposed was calculated.The activity value was obtained by subtracting the value of thepre-reaction control sample from the value of the reaction sample.

                  TABLE 3                                                         ______________________________________                                                    Feed C   Feed D   Feed E                                            % (w/w) % (w/w) % (w/w)                                                     ______________________________________                                        Extract of Evodia                                                                           --         --       1.35                                          rutaecaroa (Reference                                                         Example 1)                                                                    Casein 20 20 20                                                               Lard 5 15 15                                                                  Corn oil 5 15 15                                                              Sucrose 30 30 30                                                              Mineral mixture 4 4 4                                                         Vitamin mixture 1 1 1                                                         Cellulose powder 2 2 2                                                        Choline Chloride 0.2 0.2 0.2                                                  Corn starch 32.80 12.80 11.45                                                 Evodiamine 0 0 0.02                                                           concentration (w/w %)                                                       ______________________________________                                    

The results are shown in Table 4.

                  TABLE 4                                                         ______________________________________                                               Feed C group                                                                            Feed D group                                                                              Feed E group                                     ______________________________________                                        Calorie intake                                                                         1101.8 ± 16.0*.sup.c                                                                   1421.6 ± 21.7 .sup.                                                                    1410.9 ± 21.4                               (cal/21 days)                                                                 Last body 215.2 ± 3.6 .sup.  252.7 ± 3.5.sup.c   226.8 ± 4.3                                         weight (g)                                    Body weight 101.3 ± 2.6.sup.a   138.2 ± 2.9.sup.c   112.3 ±                                         3.8                                            increase (g)                                                                  Body weight 0.0920 ± 0.0020.sup.b 0.0972 ± 0.0011.sup.c 0.0797                                         ± 0.0029                                    increase/calorie                                                              intake (g/cal)                                                                Epididymal 3.19 ± 0.25.sup.b 4.06 ± 0.24.sup.c 2.28 ± 0.14                                           adipose tissue                                (g)                                                                           Perirenal 3.70 ± 0.30.sup.  5.68 ± 0.39.sup.c 3.06 ± 0.27                                            adipose tissue                                (g)                                                                           Lipolytic 2.75 ± 0.81.sup.b 3.19 ± 0.34.sup.b 6.35 ± 0.93                                            activity                                      (μmol/g/hr)                                                              ______________________________________                                         *Standard error of the average value                                          .sup.a,b,c The difference between Feed C or D group and Feed E group was      significant (a: P < 0.05, b: P < 0.01, c: P < 0.001).                    

The body weight increase was significantly reduced in Feed E groupcompared with that in Feed D group which had almost the same calorieintake. Feed E group showed significantly less body weight increase percalorie intake as compared not only with Feed D group but also with FeedC group which had a smaller total calorie intake.

The amounts of the perirenal adipose tissue and the epididymal adiposetissue in Feed E group were significantly smaller than those in Feed Dgroup. Further, as compared with the results on Feed C group which had asmaller total calorie intake, the amount of the epididymal adiposetissue in Feed E group was significantly smaller, and that of theperirenal adipose tissue was also somewhat smaller.

Feed E group showed significantly higher lipolytic activity as comparedwith Feed C group and Feed D group, which indicates that lipidmetabolism was improved in Feed E group. Thus, it was confirmed that theextract of Evodia rutaecarpa containing evodiamine had lipid metabolismimproving activity or anti-obesity activity.

BEST MODE FOR CARRYING OUT THE INVENTION EXAMPLE 1

Cookies (30 pieces) are prepared from the following ingredients.

    ______________________________________                                        Soft flour          100    g                                                    Starch 74 g                                                                   Water 14 g                                                                    Evodiamine 0.6 g                                                              Baking powder 2 Tsp.                                                          Salt 1/2  Tsp.                                                                Egg one                                                                       Butter 80 g                                                                   Milk 2 Tbsp.                                                                  Honey Small quantity                                                        ______________________________________                                    

EXAMPLE 2

A soft drink (10 bottles) is prepared from the following ingredients.

    ______________________________________                                               Evodiamine    1      g                                                   Vitamin C 1 g                                                                 Vitamin B1 5 mg                                                               Vitamin B2 10 mg                                                              Vitamin B6 25 mg                                                              Sugar syrup 150 g                                                             Citric acid 3 g                                                               Flavor 1 g                                                                  ______________________________________                                    

Water is added to make a volume of 1000 ml.

EXAMPLE 3

Bread (4 loaves) is prepared from the following ingredients.

    ______________________________________                                               Evodiamine    2.4    g                                                   Hard flour 1 kg                                                               Sugar 50 g                                                                    Salt 20 g                                                                     Skim milk 20 g                                                                Shortening 60 g                                                               Yeast (fresh) 30 g                                                            Yeast food 1 g                                                                Water 650 g                                                                 ______________________________________                                    

EXAMPLE 4

Tablets (300 mg/tablet) are prepared from the following ingredientsaccording to a conventional method.

    ______________________________________                                        Evodiamine              10     mg                                               Lactose 230 mg                                                                Corn starch 30 mg                                                             Synthetic aluminum silicate 12 mg                                             Carboxymethyl cellulose calcium 15 mg                                         Magnesium stearate 3 mg                                                     ______________________________________                                    

EXAMPLE 5

A powder preparation (1000 mg/package) is prepared from the followingingredients according to a conventional method.

    ______________________________________                                               Evodiamine    10     mg                                                  Lactose 800 mg                                                                Corn starch 190 mg                                                          ______________________________________                                    

EXAMPLE 6

Hard capsules (360 mg/capsule) are prepared from the followingingredients.

    ______________________________________                                        Evodiamine             10     mg                                                Lactose 230 mg                                                                Corn starch 100 mg                                                            Hydroxypropyl cellulose 20 mg                                               ______________________________________                                    

Evodiamine (10 mg) is mixed with 230 mg of lactose and 100 mg of cornstarch, and 20 mg of an aqueous solution of hydroxypropyl cellulose isadded thereto. The mixture is kneaded and then granulated according to aconventional method using an extruding granulator. The obtained granulesare packed in gelatin hard capsules.

EXAMPLE 7

Soft capsules (170 mg/capsule) are prepared from the followingingredients.

    ______________________________________                                               Evodiamine    10     mg                                                  Soybean oil 160 mg                                                          ______________________________________                                    

Evodiamine (10 mg) is mixed with 160 mg of soybean oil. The resultingmixture is packed in soft capsules according to a conventional methodusing a rotary dies automatic molding machine.

EXAMPLE 8

A feed for a mouse (ration for one month) is prepared from the followingingredients.

    ______________________________________                                        Evodiamine           0.03    g                                                  Casein 20 g                                                                   Lard 10 g                                                                     Sucrose 10 g                                                                  Mineral mixture 4 g                                                           Vitamin mixture 1 g                                                           Cellulose powder 2 g                                                          Sodium cholate 0.125 g                                                        Choline chloride 0.2 g                                                        Corn starch 52.645 g                                                        ______________________________________                                    

EXAMPLE 9

A powder preparation (1000 mg/package) is prepared from the followingingredients according to a conventional method.

    ______________________________________                                               Rutaecarpine  10     mg                                                  Lactose 800 mg                                                                Corn starch 190 mg                                                          ______________________________________                                    

EXAMPLE 10

Soft capsules (170 mg/capsule) are prepared from the followingingredients.

    ______________________________________                                        Dehydroevodiamine     10     mg                                                 Soybean oil 160 mg                                                          ______________________________________                                    

Dehydroevodiamine (10 mg) is mixed with 160 mg of soybean oil. Theresulting mixture is packed in soft capsules according to a conventionalmethod using a rotary dies automatic molding machine.

EXAMPLE 11

A feed for a mouse (ration for one month) is prepared from the followingingredients.

    ______________________________________                                        Hydroxyevodiamine     0.03    g                                                 Casein 20 g                                                                   Lard 10 g                                                                     Sucrose 10 g                                                                  Mineral mixture 4 g                                                           Vitamin mixture 1 g                                                           Cellulose powder 2 g                                                          Sodium cholate 0.125 g                                                        Choline chloride 0.2 g                                                        Corn starch 52.645 g                                                        ______________________________________                                    

EXAMPLE 12

Tea (1000 ml) is prepared from the following ingredients.

    ______________________________________                                        Extract of Evodia rutaecarpa                                                                      5         g                                                 (Reference Example 1)                                                         Tea leaves 15 g                                                             ______________________________________                                    

EXAMPLE 13

Tablets (300 mg/tablet) are prepared from the following ingredientsaccording to a conventional method.

    ______________________________________                                        Extract of Evodia rutaecarpa                                                                       50        mg                                               (Reference Example 1)                                                         Lactose 190 mg                                                                Corn starch 30 mg                                                             Synthetic aluminum silicate 12 mg                                             Carboxymethyl cellulose calcium 15 mg                                         Magnesium stearate 3 mg                                                     ______________________________________                                    

EXAMPLE 14

Chewing gum (30 pieces) is prepared from the following ingredients.

    ______________________________________                                        Extract of Evodia rutaecarpa                                                                      1         g                                                 (Reference Example 1)                                                         Gum base 25 g                                                                 Sugar 63 g                                                                    Starch syrup 10 g                                                             Flavor 1 g                                                                  ______________________________________                                    

EXAMPLE 15

Candies (20 pieces) are prepared from the following ingredients.

    ______________________________________                                        Extract of Evodia rutaecarpa                                                                      1         g                                                 (Reference Example 1)                                                         Sugar 80 g                                                                    Starch syrup 20 g                                                             Flavor 0.1 g                                                                ______________________________________                                    

EXAMPLE 16

Soft capsules (170 mg/capsule) are prepared from the followingingredients.

    ______________________________________                                        Extract of Fagara rhetza                                                                        50          mg                                                (Reference Example 2)                                                         Soybean oil 120 mg                                                          ______________________________________                                    

The extract of Fagara rhetza (50 mg) is mixed with 120 mg of soybeanoil. The resulting mixture is packed in soft capsules according to aconventional method using a rotary dies automatic molding machine.

EXAMPLE 17

Marmalade is prepared from the following ingredients.

    ______________________________________                                        Extract of Zanthoxylum rhetsa                                                                    7           g                                                (Reference Example 3)                                                         Feel of Chinese citrons 500 g                                                 Sugar 200 g                                                                 ______________________________________                                    

Juice obtained from one Chinese citron

EXAMPLE 18

A feed for sea breams is prepared from the following ingredients.

    ______________________________________                                        Extract of Araliopsis tabouensis                                                                  10         g                                                (Reference Example 4)                                                         Fish meal 25 g                                                                Chicken meal 100 g                                                            Meat and bone meal 150 g                                                      Fish soluble 25 g                                                             Soybean cake 260 g                                                            Wheat flour 125 g                                                             Corn 250 g                                                                    Wheat germ 40 g                                                               Lucerne meal 40 g                                                             Salt 5 g                                                                      Antioxidant 20 g                                                            ______________________________________                                    

REFERENCE EXAMPLE 1

Process for Producing Extract of Evodia rutaecarpa

To 2.5 kg of fruits of Evodia rutaecarpa was added 10 l of ethanol,followed by maceration for 2 days. After collection of the extract, thesame treatment was repeated twice to obtain 30 l of ethanol extract. Theethanol extract was filtered using a filter cloth (Miracloth, HoechstLtd.), and the filtrate was concentrated to dryness under reducedpressure to give 100 g of extract.

REFERENCE EXAMPLE 2

Process for Producing Extract of Fagara rhetza

To 200 g of bark of Fagara rhetza was added 1 l of ethanol, followed bymaceration for 2 days. After collection of the extract, the sametreatment was repeated twice to obtain 3 l of ethanol extract. Theethanol extract was filtered using a filter cloth (Miracloth, HoechstLtd.), and the filtrate was concentrated to dryness under reducedpressure to give 19.6 g of extract.

REFERENCE EXAMPLE 3

Process for Producing Extract of Zanthoxylum rhetsa

To 200 g of root bark of Zanthoxylum rhetsa was added 1 l of ehtanol,followed by maceration for 2 days. After collection of the extract, thesame treatment was repeated twice to obtain 3 l of ethanol extract. Theethanol extract was filtered using a filter cloth (Miracloth, HoechstLtd.), an the filtrate was concentrated to dryness under reducedpressure to give 7.1 g of extract.

REFERENCE EXAMPLE 4

Process for Producing Extract of Araliopsis tabouensis

To 250 g of bark of Araliopsis tabouensis was added 1 l of chloroform,followed by maceration for 2 days. After collection of the extract, thesame treatment was repeated twice to obtain 3 l of chloroform extract.The chloroform extract was filtered using a filter cloth (Miracloth,Hoechst Ltd.), and the filtrate was concentrated to dryness underreduced pressure to give 9.6 g of extract.

REFERENCE EXAMPLE 5

Determination of Evodiamine

The extracts obtained in Reference Examples 1-4 were respectivelydissolved in ethanol to a concentration of 0.01% (w/v). Then, 10 μl ofeach solution was subjected to high performance liquid chromatography(Shimadzu Corporation, ODS column: 4.6 mm I.D. 25 cm, mobile phase: a50% aqueous solution of acetonitrile, detection wavelength: 254 nm) todetermine the evodiamine content.

The results are shown in Table 5.

                  TABLE 5                                                         ______________________________________                                                       Evodiamine content of dried                                      Plants extract %(w/w)                                                       ______________________________________                                        Evodia rutaecarpa                                                                            1.13                                                             (Reference Example 1)                                                         Fagara rhetza 2.94                                                            (Reference Example 2)                                                         Zanthoxylum rhetsa 0.014                                                      (Reference Example 3)                                                         Araliopsis tabouensis 0.018                                                   (Reference Example 4)                                                       ______________________________________                                    

Industrial Applicability

The present invention provides a food, a drug and a feed which havelipid metabolism improving activity or anti-obesity activity.

We claim:
 1. A food having lipid metabolism improving activity oranti-obesity activity which comprises, as an active ingredient, acompound selected from the group consisting of compounds represented byformula (I): ##STR7## wherein >A--B-- represents >CR¹ --NR² -- (whereinR¹ represents hydrogen or hydroxy, and R² represents hydrogen or loweralkyl; or R¹ and R² are combined together to form a bond) or >C═N⁺(R³)-- (wherein R³ represents lower alkyl); n represents 0 when >A--B--is >CR¹ --NR² --, and represents 1 when >A--B-- is >C═N⁺ (R³)--; and X⁻represents an anion, and salts thereof (hereinafter collectivelyreferred to as evodiamine compounds).
 2. The food according to claim 1,which is obtained by adding an evodiamine compound to food materialscontaining substantially no evodiamine compound.
 3. The food accordingto claim 1, which is obtained by adding a part of a plant containing anevodiamine compound, or a ground matter, extract, a partially-purifiedproduct or a purified product containing an evodiamine compound which isobtained from said part of the plant to food materials containingsubstantially no evodiamine compound.
 4. The food according to claim 3,wherein said plant containing an evodiamine compound belongs to thefamily Rutaceae.
 5. The food according to claim 3, wherein said plantcontaining an evodiamine compound belongs to a genus selected from thegroup consisting of Evodia, Fagara, Zanthoxylum and Araliopsis.
 6. Afeed having lipid metabolism improving activity or anti-obesity activitywhich comprises an evodiamine compound as an active ingredient.
 7. Thefeed according to claim 6, which is obtained by adding an evodiaminecompound to feed materials containing substantially no evodiaminecompound.
 8. The feed according to claim 6, which is obtained by addinga part of a plant containing an evodiamine compound, or a ground matter,extract, a partially-purified product or a purified product containingan evodiamine compound which is obtained from said part of the plant tofeed materials containing substantially no evodiamine compound.
 9. Thefeed according to claim 8, wherein said plant containing an evodiaminecompound belongs to the family Rutaceae.
 10. The feed according to claim8, wherein said plant containing an evodiamine compound belongs to agenus selected from the group consisting of Evodia, Fagara, Zanthoxylumand Araliopsis.
 11. A feed additive having lipid metabolism improvingactivity or anti-obesity activity which comprises an evodiamine compoundas an active ingredient.